Exploratory Association of 5' and 3' UTRs Variants in TYMS and CCND1 with Severe Hematologic Toxicity in Pediatric...

Mexico has one of the highest incidences of childhood acute lymphoblastic leukemia worldwide and also reports one of the lowest 5-year overall survival rates; one cause is elevated treatment-related mortality from severe hematologic toxicity, a critical side effect during chemotherapy. Although association studies have identified common genetic variants linked to toxicity, the Mexican population remains incompletely explored. We performed targeted next-generation sequencing of genes involved in methotrexate and mercaptopurine metabolism in 96 Mexican children with ALL, stratified by hematologic toxicity severity according to CTCAE v5.0. Logistic regression revealed nominally significant associations between the TSER*3/TSER*2 genotype (rs45445694) in the 5' UTR of TYMS severe hematologic toxicity (overdominant model: OR = 3.21; 95% CI = 1.23-8.38; p = 0.014 and codominant model: OR = 3.31; 95% CI = 1.17-9.34; p = 0.047). Additionally, the CCND1 LD block (rs678653/rs7177) also showed nominal associations (overdominant model: OR = 2.60; 95% CI = 1.01-6.71; p = 0.044). None of these associations remained statistically significant after Bonferroni correction for multiple testing (corrected α = 0.000588). Patients with severe toxicity had lower 5-year overall survival than those without severe toxicity (70.2% vs. 90.5%; p = 0.0609), although the difference was not statistically significant. Variants in 5' and 3' UTRs regions were markedly enriched compared to coding sequences, underscoring the importance of regulatory region analysis.